Skip to main content
SpringerLink
Log in

Genomic Applications to Study Pulmonary Hypertension

  • Chapter
  • First Online:
Textbook of Pulmonary Vascular Disease

  • 217 Accesses

Abstract

As part of the World Health Organization (WHO) symposia on pulmonary hypertension, experts from both clinical and basic science arenas recommended revision of the classification scheme for pulmonary hypertension. This scheme was designed to “individualize different categories sharing similarities in pathological mechanisms, clinical presentation and therapeutic options.” The diseases that comprise pulmonary arterial hypertension (PAH) were stratified in a manner consistent with current understanding of the pathobiological processes, facilitating discussion and the enrollment in clinical trials. However, these changes simultaneously highlight our lack of understanding regarding the basic pathological mechanisms underlying the development of PAH. For example, why do radically diverse conditions such as systemic lupus erythematosus, anorexigen exposure, and HIV-1 infection result in similar pathologic changes in the lung vasculature? Why does one individual with a connective tissue disease such as scleroderma develop pulmonary vascular disease whereas another develops pulmonary fibrosis? Why do patients with PAH associated with congenital cardiac shunts have better survival than patients with idiopathic PAH (IPAH)? Clearly, the pathogenesis of PAH is complex, involving multiple modulating genes and environmental factors. Such complexity lends itself to the use of microarray technology, allowing the efficient and accurate simultaneous expression measurement of thousands of genes. Gene microarray technology has most successfully been employed in the investigation of cancer, including hematologic malignancies, and in the classification of histologically indistinct tumor types with divergent natural histories. The power of this technology has recently been directed toward the study of PAH.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Fishman AP (2001) Clinical classification of pulmonary hypertension. Clin Chest Med 22:385–391

    Article  PubMed  CAS  Google Scholar 

  2. Rich S (1998) Executive summary from the world symposium on primary pulmonary hypertension. World Health Organization, Geneva

    Google Scholar 

  3. Simonneau G, Galiè N, Rubin LJ et al (2004) Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S–12S

    Article  PubMed  Google Scholar 

  4. Simonneau G, Robbins IM, Beghetti M et al (2009) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54:s43–s54

    Article  PubMed  Google Scholar 

  5. Johnson SR, Gladman DD, Urowitz MB, Ibanez D, Granton JT (2004) Pulmonary hypertension in systemic lupus. Lupus 13:506–509

    Article  PubMed  CAS  Google Scholar 

  6. Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L (2000) Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest 117:870–874

    Article  PubMed  CAS  Google Scholar 

  7. Gross SB, Lepor NE (2000) Anorexigen-related cardiopulmonary toxicity. Rev Cardiovasc Med 1:80–89

    PubMed  CAS  Google Scholar 

  8. Fiorencis R, Zonzin P, Carraro M et al (1998) Pulmonary hypertension associated with human immunodeficiency virus infection. Report of two cases and review of the literature. G Ital Cardiol 28:1404–1408

    PubMed  CAS  Google Scholar 

  9. Stupi AM, Steen VD, Owens GR, Barnes EL, Rodnan GP, Medsger TA Jr (1986) Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 29:515–524

    Article  PubMed  CAS  Google Scholar 

  10. de Azevedo AB, Sampaio-Barros PD, Torres RM, Moreira C (2005) Prevalence of pulmonary hypertension in systemic sclerosis. Clin Exp Rheumatol 23:447–454

    PubMed  Google Scholar 

  11. Trad S, Amoura Z, Beigelman C et al (2006) Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease. Arthritis Rheum 54:184–191

    Article  PubMed  Google Scholar 

  12. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C (2005) The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 52:2125–2132

    Article  PubMed  Google Scholar 

  13. Steen VD (2005) The lung in systemic sclerosis. J Clin Rheumatol 11:40–46

    Article  PubMed  Google Scholar 

  14. McLaughlin VV, Presberg KW, Doyle RL et al (2004) Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:78S–92S

    Article  PubMed  Google Scholar 

  15. Khan J, Wei JS, Ringnér M et al (2001) Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 7:673–679

    Article  PubMed  CAS  Google Scholar 

  16. Bittner M, Meltzer P, Chen Y et al (2000) Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 406:536–540

    Article  PubMed  CAS  Google Scholar 

  17. Bhattacharjee A, Richards WG, Staunton J et al (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A 98:13790–13795

    Article  PubMed  CAS  Google Scholar 

  18. Bullinger L, Döhner K, Bair E et al (2004) Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350:1605–1616

    Article  PubMed  CAS  Google Scholar 

  19. Valk PJ, Verhaak RG, Beijen MA et al (2004) Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350:1617–1628

    Article  PubMed  CAS  Google Scholar 

  20. Fantozzi I, Huang W, Zhang J et al (2005) Divergent effects of BMP-2 on gene expression in pulmonary artery smooth muscle cells from normal subjects and patients with idiopathic pulmonary arterial hypertension. Exp Lung Res 31:783–806

    Article  PubMed  CAS  Google Scholar 

  21. Bull TM, Coldren CD, Moore M et al (2004) Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med 170:911–919

    Article  PubMed  Google Scholar 

  22. Hoshikawa Y, Nana-Sinkam P, Moore MD et al (2003) Hypoxia induces different genes in the lungs of rats compared with mice. Physiol Genomics 12:209–219

    PubMed  CAS  Google Scholar 

  23. Kwapiszewska G, Wilhelm J, Wolff S et al (2005) Expression profiling of laser-microdissected intrapulmonary arteries in hypoxia-induced pulmonary hypertension. Respir Res 6:109–124

    Article  PubMed  Google Scholar 

  24. Buermans HP, Redout EM, Schiel AE et al (2005) Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 21:314–323

    Article  PubMed  CAS  Google Scholar 

  25. Dempsey EC, Stenmark KR, McMurtry IF, O’Brien RF, Voelkel NF, Badesch DB (1990) Insulin-like growth factor I and protein kinase C activation stimulate pulmonary artery smooth muscle cell proliferation through separate but synergistic pathways. J Cell Physiol 144:159–165

    Article  PubMed  CAS  Google Scholar 

  26. Fink L, Kohlhoff S, Stein MM et al (2002) cDNA array hybridization after laser-assisted microdissection from nonneoplastic tissue. Am J Pathol 160:81–90

    Article  PubMed  CAS  Google Scholar 

  27. Leonard MO, Howell K, Madden SF et al (2008) Hypoxia selectively activates the CREB family of transcription factors in the in vivo lung. Am J Respir Crit Care Med 178:977–983

    Article  PubMed  CAS  Google Scholar 

  28. Geraci MW, Moore M, Gesell T et al (2001) Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res 88:555–562

    PubMed  CAS  Google Scholar 

  29. Razani B, Schlegel A, Liu J, Lisanti MP (2001) Caveolin-1, a putative tumour suppressor gene. Biochem Soc Trans 29:494–499

    Article  PubMed  CAS  Google Scholar 

  30. Lee SW, Reimer CL, Oh P, Campbell DB, Schnitzer JE (1998) Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene 16:1391–1397

    Article  PubMed  CAS  Google Scholar 

  31. Achcar RO, Demura Y, Rai PR et al (2006) Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension. Chest 129:696–705

    Article  PubMed  CAS  Google Scholar 

  32. Zhang S, Fantozzi I, Tigno DD et al (2003) Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:L740–L754

    PubMed  CAS  Google Scholar 

  33. Humbert M, Monti G, Brenot F et al (1995) Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151:1628–1631

    PubMed  CAS  Google Scholar 

  34. Isern RA, Yaneva M, Weiner E et al (1992) Autoantibodies in patients with primary pulmonary hypertension: association with anti-Ku. Am J Med 93:307–312

    Article  PubMed  CAS  Google Scholar 

  35. Voelkel NF, Tuder R (1994) Interleukin-1 receptor antagonist inhibits pulmonary hypertension induced by inflammation. Ann N Y Acad Sci 725:104–109

    Article  PubMed  CAS  Google Scholar 

  36. Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM (1998) Primary pulmonary hypertension between inflammation and cancer. Chest 114:225S–230S

    Article  PubMed  CAS  Google Scholar 

  37. Vizza CD, Letizia C, Sciomer S et al (2005) Increased plasma levels of adrenomedullin, a vasoactive peptide, in patients with end-stage pulmonary disease. Regul Pept 124:187–193

    Article  PubMed  CAS  Google Scholar 

  38. Sheppard D (2004) Fishing in the bloodstream: insights into the mechanisms of pulmonary hypertension? Am J Respir Crit Care Med 170:827–828

    Article  PubMed  Google Scholar 

  39. Grigoryev DN, Mathai SC, Fisher MR et al (2008) Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. Transl Res 151:197–207

    Article  PubMed  CAS  Google Scholar 

  40. Morrell NW, Yang X, Upton PD et al (2001) Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β1 and bone morphogenetic proteins. Circulation 104:790–795

    Article  PubMed  CAS  Google Scholar 

  41. Korstjens IJ, Rouws CH, van der Laarse WJ (2002) Van der ZL, Stienen GJ. Myocardial force development and structural changes associated with monocrotaline induced cardiac hypertrophy and heart failure. J Muscle Res Cell Motil 23:93–102

    Article  PubMed  CAS  Google Scholar 

  42. Spees JL, Whitney MJ, Sullivan DE et al (2008) Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension. FASEB J 22:1226–1236

    Article  PubMed  CAS  Google Scholar 

  43. Damania B, Desrosiers RC (1929) Simian homologues of human herpesvirus 8. Philos Trans R Soc Lond B Biol Sci 356:535–543

    Google Scholar 

  44. Desrosiers RC, Sasseville VG, Czajak SC et al (1997) A herpesvirus of rhesus monkeys related to the human Kaposi’s sarcoma-associated herpesvirus. J Virol 71:9764–9769

    PubMed  CAS  Google Scholar 

  45. Cool CD, Rai MD, Yeager ME et al (2003) Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 349:1113–1122

    Article  PubMed  CAS  Google Scholar 

  46. Boshoff C, Endo Y, Collins PD et al (1997) Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278:290–294

    Article  PubMed  CAS  Google Scholar 

  47. Guo HG, Sadowska M, Reid W, Tschachler E, Hayward G, Reitz M (2003) Kaposi’s sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J Virol 77:2631–2639

    Article  PubMed  CAS  Google Scholar 

  48. Estep RD, Axthelm MK, Wong SW (2003) A G protein-coupled receptor encoded by rhesus rhadinovirus is similar to ORF74 of Kaposi’s sarcoma-associated herpesvirus. J Virol 77:1738–1746

    Article  PubMed  CAS  Google Scholar 

  49. Bais C, Van Geelen A, Eroles P et al (2003) Kaposi’s sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/KDR. Cancer Cell 3:131–143

    Article  PubMed  CAS  Google Scholar 

  50. Yang TY, Chen SC, Leach MW et al (2000) Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi’s sarcoma. J Exp Med 191:445–454

    Article  PubMed  CAS  Google Scholar 

  51. Galambos C, Montgomery J, Jenkins FJ (2006) No role for Kaposi sarcoma-associated herpesvirus in pediatric idiopathic pulmonary hypertension. Pediatr Pulmonol 41:122–125

    Article  PubMed  Google Scholar 

  52. Laney AS, De M, Peters JS et al (2005) Kaposi sarcoma-associated herpesvirus and primary and secondary pulmonary hypertension. Chest 127:762–767

    Article  PubMed  Google Scholar 

  53. Katano H, Ito K, Shibuya K, Saji T, Sato Y, Sata T (2001) Lack of human herpesvirus 8 infection in lungs of Japanese patients with primary pulmonary hypertension. J Infect Dis 191:743–745

    Article  Google Scholar 

  54. Nicastri E, Vizza CD, Carletti F et al (2005) Human herpesvirus 8 and pulmonary hypertension. Emerg Infect Dis 11:1480–1482

    PubMed  Google Scholar 

  55. Henke-Gendo C, Mengel M, Hoeper MM, Alkharsah K, Schulz TF (1915) Absence of Kaposi’s sarcoma-associated herpesvirus in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 172:1581–1585

    Article  Google Scholar 

  56. Bull TM, Meadows CA, Coldren CD et al (2008) Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells. Am J Respir Cell Mol Biol 39:706–716

    Article  PubMed  CAS  Google Scholar 

  57. Hardie WD, Korfhagen TR, Sartor MA et al (2007) Genomic profile of matrix and vasculature remodeling in TGF-α induced pulmonary fibrosis. Am J Respir Cell Mol Biol 37:309–321

    Article  PubMed  CAS  Google Scholar 

  58. Tada Y, Majka S, Carr M et al (2007) Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH. Am J Physiol Lung Cell Mol Physiol 292:L1556–L1563

    Article  PubMed  CAS  Google Scholar 

  59. Irizarry RA, Ladd-Acosta C, Carvalho B et al (2008) Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Res 18:780–790

    Article  PubMed  CAS  Google Scholar 

  60. Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41:178–186

    Article  PubMed  CAS  Google Scholar 

  61. Li W, Ruan K (2009) MicroRNA detection by microarray. Anal Bioanal Chem 394:1117–1124

    Article  PubMed  CAS  Google Scholar 

  62. Cook EH Jr, Scherer SW (2008) Copy-number variations associated with neuropsychiatric conditions. Nature 455:919–923

    Article  PubMed  CAS  Google Scholar 

  63. Wang W, Carvalho B, Miller ND, Pevsner J, Chakravarti A, Irizarry RA (2008) Estimating genome-wide copy number using allele-specific mixture models. J Comput Biol 15:857–866

    Article  PubMed  CAS  Google Scholar 

  64. Blencowe BJ, Ahmad S, Lee LJ (2009) Current-generation high-throughput sequencing: deepening insights into mammalian transcriptomes. Genes Dev 23:1379–1386

    Article  PubMed  CAS  Google Scholar 

  65. Chatterjee SK, Zetter BR (2005) Cancer biomarkers: knowing the present and predicting the future. Future Oncol 1:37–50

    Article  PubMed  CAS  Google Scholar 

  66. Reis-Filho JS, Westbury C, Pierga JY (2006) The impact of expression profiling on prognostic and predictive testing in breast cancer. J Clin Pathol 59:225–231

    Article  PubMed  CAS  Google Scholar 

  67. Li Y, Elashoff D, Oh M et al (2006) Serum circulating human mRNA profiling and its utility for oral cancer detection. J Clin Oncol 24:1754–1760

    Article  PubMed  CAS  Google Scholar 

  68. Lacayo NJ, Meshinchi S, Kinnunen P et al (2004) Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes. Blood 104:2646–2654

    Article  PubMed  CAS  Google Scholar 

  69. Murali S (2006) Pulmonary arterial hypertension. Curr Opin Crit Care 12:228–234

    Article  PubMed  Google Scholar 

  70. Woodcock J (2005) Pharmacogenetics: on the road to ’personalized medicine’. FDA Consum 39:44

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary Sciences & Critical Care Medicine, University of Colorado, 12700 East 19th Ave, Research 2, 9th Flr., Aurora, CO, 80045, USA

    Todd M. Bull

Authors
  1. Todd M. Bull
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark W. Geraci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Todd M. Bull .

Editor information

Editors and Affiliations

  1. Departments of Medicine, COMRB Rm. 3131 (MC 719), University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, 60612, Illinois, USA

    Jason X. -J. Yuan

  2. 310 Admin.Office Building (MC 672), University of Illinois at Chicago, 1737 W. Polk Street, Suite 310, Chicago, 60612, Illinois, USA

    Joe G.N. Garcia

  3. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0623, California, USA

    John B. West

  4. Dept. Pulmonary & Critical Care Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Charles A. Hales

  5. Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stuart Rich

  6. Department of Medicine, University of Chicago School of Medicine, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stephen L. Archer

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Bull, T.M., Geraci, M.W. (2011). Genomic Applications to Study Pulmonary Hypertension. In: Yuan, JJ., Garcia, J., West, J., Hales, C., Rich, S., Archer, S. (eds) Textbook of Pulmonary Vascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-87429-6_40

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-87429-6_40

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-87428-9

  • Online ISBN: 978-0-387-87429-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation